1. Field of the Invention
The present invention relates to processes for preparing carrier particles for use in dry powder formulations for inhalation. The present invention also relates to carrier particles produced by such a process and dry powder formulations prepared with such carrier particles. The present invention further relates to methods for the treatment and/or prevention of certain diseases and conditions by administering such a dry powder formulation.
2. Discussion of the Background
Dry powder inhalation (DPI) drug therapy has been used for many years to treat respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. Compared to oral drug intake, only relatively small doses are needed for effective therapy as first pass metabolism is significantly reduced. Such small doses reduce the body's exposure to the drug and minimize side effects. Systemic adverse effects are also reduced as topical lung delivery takes the drug directly to the site of action. Lower dosage regimens may also provide considerable cost savings, particularly where expensive therapeutic agents are concerned.
Dry powder forms are typically formulated by mixing the drug in micronized form with coarse carrier particles, giving rise to an ordered mixture where the micronized active particles adhere to the surface of the carrier particles whilst in the inhaler device. The carrier makes the micronized powder less cohesive and improves its flowability, making it easier to handle the powder during the manufacturing process (pouring, filling, etc.).
During inhalation, the drug particles separate from the surface of carrier particles and penetrate into the lower lungs, while the larger carrier particles are mostly deposited in the oropharyngeal cavity.
The re-dispersion of drug particles from the carrier surface is regarded as the most critical factor which governs the availability of the medicament to the lungs. This will depend on the mechanical stability of the powder mix and the way this is influenced by the adhesion characteristics between the drug and the carrier and the external forces required to break up the non covalent bonds formed between adhering particles. Too strong bonds between adhering particles may indeed prevent the separation of the micronized drug particles from the surface of carrier particles.
Different approaches aimed at modulating the adhesion have been proposed in the art to promote the release of the drug particles from the carrier particles and, hence, to increase the respirable fraction. For example, the use of additives with lubricant or anti-adherent properties has been suggested as a solution of the technical problem. A particularly useful additive has been found to be magnesium stearate.
The benefit of using magnesium stearate in dry powders is taught in U.S. Pat. No. 6,528,096, which is incorporated herein by reference in its entirety. Specifically, it discloses that said additive can be used to alter the surface properties of carrier particles and thereby improve the properties of dry powder formulations. U.S. Pat. No. 6,528,096 discloses an “advantageous relationship” between surface coating carrier particles with magnesium stearate and the fine particle fraction (respirable fraction) of the emitted dose. Critical to the working of this effect is the need to ensure a coating of magnesium stearate over more than 15% of the surface of the carrier particles. In the examples of U.S. Pat. No. 6,528,096, percentages of coating up to 38% are disclosed.
However it would be highly advantageous to provide a process capable of giving rise to higher percentages of surface coating, as it would allow the improvement of the performances of the formulation by using a lower amount of additive.